This proposal involves studies to develop methods for the total synthesis of the didemnin depsipeptides, a group of antibiotics isolated from Caribbean tunicates. The antibiotics are of interest due to their significant antiviral and antitumor activities at low dosage levels. The antibiotics are characterized by a 23-membered ring composed of L-threonine, the novel amino acid epistatine, a 4-hydroxy-3-keto-2, 5-dimethylhexanoic acid of unknown configuration, L-leucine, L-proline, and N,O-dimethyl-1-tyrosine. Various amino acid or peptide units attached to the alpha-amino group of L-threonine constitute the didemnins A, B, and C. The project will focus on the preparation, by methods that afford stereochemical control, of the novel 4-hydroxy-3-keto-2,5-dimethylhexanoic acid common to the antibiotics. The incorporation of this unit, along with the novel amino acid epistatine, into a linear depsipeptide corresponding to the cyclic portion of the antibiotic will be studied. Cyclization of the linear precursor to provide the cyclic component of the didemnins will be investigated. The cyclic depsipeptide will contain protection at the amino function of L-threonine, which upon deprotection will allow incorpoation of amino acid or dipeptide units at this position to furnish didemnins A, B, and C or analogues thereof. The synthetic didemnins will be evaluated for antitumor and antiviral activities.